1. Field of the Invention
The present invention relates to novel classes of compounds which are inhibitors of interleukin-1xcex2 converting enzyme and related proteases (xe2x80x9cICE/ced-3 family of cysteine proteasesxe2x80x9d), as well as pharmaceutical compositions comprising these compounds and to methods of using such pharmaceutical compositions.
2. Description of the Related Art
Interleukin 1 (xe2x80x9cIL-1xe2x80x9d) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J. H. et al., Immunology Today 7:45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response. Mosely, B. S. et al., Proc. Nat. Acad. Sci. 84:4572-4576 (1987); Lonnemann, G. et al., Eur. J. Immunol. 19:1531-1536 (1989).
IL-1xcex2 is synthesized as a biologically inactive precursor, proIL-1xcex2. P. ProIL-1 xcex2 is cleaved by a cysteine protease called interleukin-1 xcex2 converting enzyme (xe2x80x9cICExe2x80x9d) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P. R. et al., J. Biol. Chem. 265:14526-14528 (1992); A. D. Howard et al., J. Immunol. 147:2964-2969 (1991).
ICE is a cysteine protease localized primarily in monocytes. In addition to promoting the pro-inflammatory and immunoregulatory properties of IL-1xcex2, ICE, and particularly its homologues, also appear to be involved in the regulation of cell death or apoptosis. Yuan, J. et al., Cell 75:641-652 (1993); Miura, M. et al., Cell 75:653-660 (1993); Nett-Giordalisi, M. A. et al., J. Cell Biochem. 17B:117 (1993). In particular, ICE or ICE/ced-3 homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer""s and Parkinson""s disease. Marx, J. and M. Baringa, Science 259:760-762 (1993); Gagliardini, V. et al., Science 263:826-828 (1994).
Thus, disease states in which inhibitors of the ICE/ced-3 family of cysteine proteases may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, ischemic diseases such as the myocardial infarction, stroke and ischemic kidney disease; immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain neurodegenerative diseases, such as Alzheimer""s and Parkinson""s disease. Such inhibitors are also useful for the repopulation of hematopoietic cells following chemo- and radiation therapy and for prolonging organ viability for use in transplantation.
ICE/ced-3 inhibitors represent a class of compounds useful for the control of the above-listed disease states. Peptide and peptidyl inhibitors of ICE have been described. However, such inhibitors have been typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J. J. and D. W. Norbeck, in Drug Discovery Technologies, C. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. These undesirable properties have hampered their development into effective drugs.
Accordingly, the need exists for compounds that can effectively inhibit the action of the ICE/ced-3 family of proteases, for use as agents for preventing unwanted apoptosis, and for treating chronic and acute forms of IL-1 mediated diseases such as inflammatory, autoimmune or neurodegenerative diseases. The present invention satisfies this need and provides further related advantages.
In general, the compounds of this invention incorporate a sulfonamido (NHSO2) or sulfinamido (NHSO) modified (N-substituted)oxamyl group as a dipeptide mimetic. The resulting compounds exhibit improved properties relative to their peptidic counterparts, for example, such as improved cell penetration or improved absorption and metabolic stability resulting in enhanced bioavailability.
One aspect of the instant invention is the compounds of the following Formula I: 
wherein A, B, R, R1, R1xe2x80x2, p and q are as defined below, as well as pharmaceutically acceptable salts thereof.
A further aspect of the instant invention is a pharmaceutical composition comprising a compound of the above Formula I and a pharmaceutically-acceptable carrier therefor.
Another aspect of this invention involves a method for treating an autoimmune disease comprising administering an effective amount of a pharmaceutical composition discussed above to a patient in need of such treatment.
Yet another aspect of the instant invention is a method for treating an inflammatory disease comprising administering an effective amount of a pharmaceutical composition discussed above to a patient in need of such treatment.
A further aspect of the instant invention is a method for treating a neurodegenerative disease comprising administering an effective amount of a pharmaceutical composition discussed above to a patient in need of such treatment.
Another aspect of the instant invention is a method of preventing ischemic injury to a patient suffering from a disease associated with ischemic injury comprising administering an effective amount of the pharmaceutical composition discussed above to a patient in need of such treatment.
A further aspect of the instant invention is a method for expanding of hematopoietic cell populations and/or enhancing their survival by contacting the cells with an effective amount of the pharmaceutical composition discussed above. Cell populations included in the method of the invention include (but are not limited to) granulocytes, monocytes, erthrocytes, lymphocytes and platelets for use in cell transfusions.
An alternate aspect of the instant invention is a method of prolonging the viability of an organ that has been removed from the donor for the purpose of a future transplantation procedure, which comprises applying an effective amount of the pharmaceutical composition discussed above to the organ, thereby prolonging the viability of the organ as compared to an untreated organ. The organ may be an intact organ, or isolated cells derived from an organ (e.g., isolated pancreatic islet cells, isolated dopaminergic neurons, blood or hematopoietic cells).
These and other aspects of this invention will be evident upon reference to the following detailed description.
As mentioned above, one aspect of the instant invention is the compounds of the Formula I: 
wherein:
A is a natural or unnatural amino acid of Formula IIa-i: 
B is a hydrogen atom, a deuterium atom, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, 2-benzoxazolyl, substituted 2-oxazolyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(1 or 2-naphthyl), (CH2)n(substituted 1 or 2-naphthyl), (CH2)n(heteroaryl), (CH2)n(substituted heteroaryl), halomethyl, CO2R12, CONR13R14, CH2ZR15, CH2OCO(aryl), CH2OCO(heteroaryl), or CH2OPO(R16)R7, where Z is an oxygen or a sulfur atom, or B is a group of the Formula IIIa-c: 
p is 1 or 2;
q is 1 or 2;
R and R1 are the same or different and independently alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, substituted (1 or 2 naphthyl)alkyl, heterocycle, substituted heterocycle, (heterocycle)alkyl, substituted (heterocycle)alkyl, R1a(R1b)N or R1cO;
R1xe2x80x2 is hydrogen, alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocycle or substituted heterocycle;
or R1 and R1xe2x80x2 taken together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;
and wherein:
R1a and R1b are the same or different and, at each occurrence, independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, substituted (1 or 2 naphthyl)alkyl, heteroaryl, substituted heteroaryl, (heteroaryl)alkyl, or substituted (heteroaryl)alkyl, with the proviso that R1a and R1b cannot both be hydrogen;
R1c is, at each occurrence, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, substituted (1 or 2 naphthyl)alkyl, heteroaryl, substituted heteroaryl, (heteroaryl)alkyl, or substituted (heteroaryl)alkyl;
R3 is lower alkyl, cycloalkyl, phenyl, substituted phenyl, (CH2)nNH2, (CH2)nNHCOR9, (CH2)nN(Cxe2x95x90NH)NH2, (CH2)mCO2R2, (CH2)mOR10, (CH2)mSR11, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(l or 2-naphthyl) or (CH2)n(heteroaryl), wherein heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazinyl, pyrimidyl, triazinyl, tetrazolyl, and indolyl;
R3a is hydrogen or methyl, or R3 and R3a taken together are xe2x80x94(CH2)dxe2x80x94 where d is an integer from 2 to 6;
R4 is phenyl, substituted phenyl, (CH2)mphenyl, (CH2)m(substituted phenyl), cycloalkyl, or benzofused cycloalkyl;
R5 is hydrogen, lower alkyl, cycloalkyl, phenyl, substituted phenyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R6 is hydrogen, fluorine, oxo, lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(1 or 2-naphthyl), OR10, SR11 or NHCOR9;
R7 is hydrogen, oxo (i.e., xe2x95x90O), lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R8 is lower alkyl, cycloalkyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(1 or 2-naphthyl), or COR9;
R9 is hydrogen, lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(1 or 2-naphthyl), OR2, or NR13R14;
R10 is hydrogen, lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R11 is lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R12 is lower alkyl, cycloalkyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R13 is hydrogen, lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R14 is hydrogen or lower alkyl;
or R13 and R14 taken together form a five to seven membered carbocyclic or heterocyclic ring, such as morpholine, or N-substituted piperazine;
R15 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(1 or 2-naphthyl), or (CH2)n(heteroaryl);
R16 and R17 are independently lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, phenylalkyl, substituted phenylalkyl, or (cycloalkyl)alkyl;
R18 and R19 are independently hydrogen, alky, phenyl, substituted phenyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or R18 and R19 taken together are xe2x80x94(CHxe2x95x90CH)2xe2x80x94;
R20 is hydrogen, alkyl, phenyl, substituted phenyl, (CH2)nphenyl, (CH2)n(substituted phenyl);
R21, R22 and R23 are independently hydrogen, or alkyl;
X is CH2, (CH2)2, (CH2)3, or S;
Y1 is O or NR23;
Y2 is CH2, O, or NR23;
a is 0 or 1 and b is 1 or 2, provided that when a is 0 then b is 1;
c is 1 or 2, provided that when c is 1 then a is 0 and b is 1;
m is 1 or 2; and
n is 1, 2, 3or 4;
or a pharmaceutically acceptable salt thereof.
As used herein, the term xe2x80x9calkylxe2x80x9d means a straight or branched C1 to C10 carbon chain, such as methyl, ethyl, tert-butyl, iso-propyl, n-octyl, and the like. The term xe2x80x9clower alkylxe2x80x9d means a straight chain or branched C1 to C6 carbon chain, such as methyl, ethyl, iso-propyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a mono-, bi-, or tricyclic ring that is either fully saturated or partially unsaturated. Examples of such a ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, cis- or trans decalin, bicyclo[2.2.1]hept-2-ene, cyclohex-1-enyl, cyclopent-1-enyl, 1,4-cyclooctadienyl, and the like.
The term xe2x80x9c(cycloalkyl)alkylxe2x80x9d means the above-defined alkyl group substituted with one of the above cycloalkyl rings. Examples of such a group include (cyclohexyl)methyl, 3-(cyclopropyl)-n-propyl, 5-(cyclopentyl)hexyl, 6-(adamantyl)hexyl, and the like.
The term xe2x80x9csubstituted phenylxe2x80x9d specifies a phenyl group substituted with one or more substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, trifluoromethyl, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(lower alkyl)carboxamide, protected N-(lower alkyl)carboxamide, N,N-di(lower alkyl)carboxamide, N-((lower alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or by a substituted or unsubstituted phenyl group, such that in the latter case a biphenyl or naphthyl group results, or wherein two adjacent alkyl substituents on the substituted phenyl ring taken together form a cycloalkyl to yield, for example, tetrahydronaphthyl or indanyl.
Examples of the term xe2x80x9csubstituted phenylxe2x80x9d includes a mono-, di-, tri-, tetra- or penta(halo)phenyl group such as 2-, 3- or 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-,3- or 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-, 3- or 4-fluorophenyl, 2,4,6-trifluorophenyl, 2,3,5,6-tetrafluorophenyl, 2,3,4,5-tetrafluorophenyl, 2,3,4,5,6-pentafluorophenyl, and the like; a mono or di(hydroxy)phenyl group such as 2-, 3-, or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2-, 3-, or 4-nitrophenyl; a cyanophenyl group, for example, 2-,3- or 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as 2-, 3-, or 4-methylphenyl, 2,4-dimethylphenyl, 2-, 3- or 4-(iso-propyl)phenyl, 2-, 3-, or 4-ethylphenyl, 2-, 3- or 4-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 2-, 3- or 4-(iso-propoxy)phenyl, 2-, 3- or 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 2-, 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 2-, 3- or 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 2-, 3- or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-, 3- or 4-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 2, 3 or 4-(N-(methylsulfonylamino))phenyl. Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like.
The term xe2x80x9cphenylalkylxe2x80x9d means one of the above phenyl groups attached to one of the above-described alkyl groups, and the term xe2x80x9csubstituted phenylalkylxe2x80x9d means that either the phenyl or the alkyl, or both, are substituted with one or more of the above-defined substituents. Examples of such groups include 2-phenyl-l-chloroethyl, 2-(4xe2x80x2-methoxyphenyl)ethyl, 4-(2xe2x80x2,6xe2x80x2-dihydroxy phenyl)n-hexyl, 2-(5xe2x80x2-cyano-3xe2x80x2-methoxyphenyl)n-pentyl, 3-(2xe2x80x2,6xe2x80x2-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl, 6-(4xe2x80x2-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4xe2x80x2-aminomethylphenyl)-3-(aminomethyl)n-pentyl, 5-phenyl-3-oxo-n-pent-1-yl, (4-hydroxynapth-2-yl)methyl, and the like.
The term xe2x80x9csubstituted naphthylxe2x80x9d means a naphthyl group substituted with one or more of the above-identified substituents, and the term xe2x80x9c(1 or 2 naphthyl)alkylxe2x80x9d means a naphthyl (1 or 2) attached to one of the above-described alkyl groups.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d refer to the fluoro, chloro, bromo or iodo groups. These terms may also be used to describe one or more halogens, which are the same or different. Preferred halogens in the context of this invention are chloro and fluoro.
The term xe2x80x9carylxe2x80x9d refers to aromatic five and six membered carbocyclic rings. Six membered rings are preferred.
The term xe2x80x9cheteroarylxe2x80x9d denotes optionally substituted aromatic five-membered or six-membered heterocyclic rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen atoms, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
The following ring systems are representative examples of the heterocyclic radicals denoted by the term xe2x80x9cheteroarylxe2x80x9d (whether substituted or unsubstituted): thienyl, furyl, pyrrolyl, pyrrolidinyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, triazinyl, thiadiazinyl tetrazolo, 1,5-[b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example, benzoxazolyl, benzothiazolyl, benzimidazolyl and indolyl.
The term xe2x80x9cheterocyclexe2x80x9d (also referred to herein as a xe2x80x9cheterocycle ringxe2x80x9d) means a 5- to 7-membered monocyclic heterocyclic ring that is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the aromatic heteroaryls listed above, heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
The terms xe2x80x9cheteroarylalkylxe2x80x9d and xe2x80x9cheterocyclealkylxe2x80x9d mean an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl, such as xe2x80x94CH2thienyl and the like, or with a heterocycle, such as xe2x80x94CH2morpholinyl and the like, respectively.
Substituents for the above optionally substituted heteroaryl and heterocycle rings are from one to three halo, trihalomethyl, amino, protected amino, amino salts, mono-substituted amino, di-substituted amino, carboxy, protected carboxy, carboxylate salts, hydroxy, protected hydroxy, salts of a hydroxy group, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and substituted phenylalkyl groups.
Substituents for the heteroaryl and heterocycle group are as defined above, or as set forth below. As used in conjunction with the above substituents for heteroaryl and heterocycle rings, xe2x80x9ctrihalomethylxe2x80x9d can be trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl, xe2x80x9clower alkoxyxe2x80x9d means a C1 to C4 alkoxy group, similarly, xe2x80x9clower alkylthioxe2x80x9d means a C1 to C4 alkylthio group. The term xe2x80x9csubstituted lower alkylxe2x80x9d means the above-defined lower alkyl group substituted from one to three times by a hydroxy, protected hydroxy, amino, protected amino, cyano, halo, trifluoromethyl, mono-substituted amino, di-substituted amino, lower alkoxy, lower alkylthio, carboxy, protected carboxy, or a carboxy, amino, and/or hydroxy salt.
As used in conjunction with the substituents for the heteroaryl and heterocycle rings, the terms xe2x80x9csubstituted (cycloalkyl)alkylxe2x80x9d and xe2x80x9csubstituted cycloalkylxe2x80x9d are as defined above substituted with the same groups as listed for a xe2x80x9csubstituted alkylxe2x80x9d group. The term xe2x80x9c(monosubstituted)aminoxe2x80x9d refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, alkyl, substituted alkyl, Cl to C7 acyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C2 to C7 alkynyl, C7 to C16 alkylaryl, C7 to to C16 substituted alkylaryl and heteroaryl group. The (monosubstituted)amino can additionally have an amino-protecting group as encompassed by the term xe2x80x9cprotected (monosubstituted)amino.xe2x80x9d The term xe2x80x9c(disubstituted)aminoxe2x80x9d refers to amino groups with two substituents chosen from the group consisting of phenyl, substituted phenyl, alkyl, substituted alkyl, Cl to C7 acyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C7 to C16 alkylaryl, C7 to C16 substituted alkylaryl and heteroaryl. The two substituents can be the same or different. The term xe2x80x9cheteroaryl(alkyl)xe2x80x9d denotes an alkyl group as defined above, substituted at any position by a heteroaryl group, as above defined.
Furthermore, the above optionally substituted five-membered or six-membered heterocyclic rings, and the above cycloalkyl rings, can optionally be fused to a aromatic 5-membered or 6-membered aryl or heteroaryl ring system. For example, the rings can be optionally fused to an aromatic 5-membered or 6-membered ring system such as a pyridine or a triazole system, and preferably to a benzene ring.
The term xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d encompasses those salts that form with the carboxylate anions and includes salts formed with the organic and inorganic cations such as those chosen from the alkali and alkaline earth metals, (for example, lithium, sodium, potassium, magnesium, barium and calcium); and ammonium ion; and the organic cations (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzyl-ammonium, dibenzylethylenediammonium, and like cations.) Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, the protonated forms of basic amino acids such as glycine, omithine, histidine, phenylglycine, lysine, and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. A preferred cation for the carboxylate anion is the sodium cation. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and includes organic or inorganic acids. Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, famaric, palmitic, cholic, pamoic, mucic, D-glutarnic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and the like acids.
The compounds of Formula I may also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention.
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include t-butyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, xcex2-(trimethylsilyl)ethyl, xcex2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)-propenyl and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in C. B. Reese and E. Haslam, xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, respectively, and T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 5, each of which is incorporated herein by reference. A related term is xe2x80x9cprotected carboxy,xe2x80x9d which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl (THP), 2-methoxyprop-2-yl, 1-ethoxyeth-1-yl, methoxymethyl, xcex2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, 2,2,2-trichloroethoxycarbonyl, and the like.
Further examples of hydroxy-protecting groups are described by C. B. Reese and E. Haslam, xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Second Edition, John Wiley and Sons, New York, N.Y., 1991, Chapters 2 and 3. A preferred hydroxy-protecting group is the tetrahydropyranyl (THP) group. The related term xe2x80x9cprotected hydroxyxe2x80x9d denotes a hydroxy group bonded to one of the above hydroxy-protecting groups.
The term xe2x80x9camino-protecting groupxe2x80x9d as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule. The term xe2x80x9cprotected (monosubstituted)aminoxe2x80x9d means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
Examples of such amino-protecting groups include the formyl (xe2x80x9cForxe2x80x9d) group, the trityl group, the phthalimido group, the trichloroacetyl group, the trifluoroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type protecting groups, such as t-butoxycarbonyl(xe2x80x9cBocxe2x80x9d), 2-(4-biphenylyl)propyl-2-oxycarbonyl(xe2x80x9cBpocxe2x80x9d), 2-phenylpropyl-2-oxycarbonyl(xe2x80x9cPocxe2x80x9d), 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenylethyl-1-oxycarbonyl, 1,1-diphenylpropyl-1-oxycarbonyl, 2-(3,5-dimethoxyphenyl)propyl-2-oxycarbonyl(xe2x80x9cDdzxe2x80x9d), 2-(p-toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyl-oxycarbonyl, cyclohexanyloxy-carbonyl, 1-methyl-cyclohexanyloxy-carbonyl, 2-methylcyclohexanyl-oxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, 9-fluorenyl-methoxycarbonyl(xe2x80x9cFmocxe2x80x9d), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl-oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, isobomyloxycarbonyl, 1-piperidyloxycarbonyl, benzyl-oxycarbonyl(xe2x80x9cCbzxe2x80x9d), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, xcex1-2,4,5,-tetramethylbenzyl-oxycarbonyl(xe2x80x9cTmzxe2x80x9d), 4-methoxybenzyloxycarbonyl, 4-fluorobenzyl-oxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbony, 2-chlorobenzyloxy-carbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxy-carbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 4-(decyloxy)benzyloxy-carbonyl and the like; the benzoylmethylsulfonyl group, the 2,2,5,7,8-pentamethylchroman-6-sulfonyl group (xe2x80x9cPMCxe2x80x9d), the dithiasuccinoyl (xe2x80x9cDtsxe2x80x9d) group, the 2-(nitro)phenyl-sulfenyl group (xe2x80x9cNpsxe2x80x9d), the diphenylphosphine oxide group, and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Preferred amino-protecting groups are Boc, Cbz and Fmoc. Further examples of amino-protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 7, M. Bodanzsky, xe2x80x9cPrinciples of Peptide Synthesis,xe2x80x9d 1st and 2nd revised Ed., Springer-Verlag, New York, N.Y., 1984 and 1993, and J. M. Stewart and J. D. Young, xe2x80x9cSolid Phase Peptide Synthesis,xe2x80x9d 2nd Ed., Pierce Chemical Co., Rockford, Ill., 1984, E. Atherton and R. C. Shephard, xe2x80x9cSolid Phase Peptide Synthesis-A Practical Approachxe2x80x9d IRL Press, Oxford, England (1989), each of which is incorporated herein by reference. The related term xe2x80x9cprotected aminoxe2x80x9d defines an amino group substituted with an amino-protecting group discussed above.
The terms xe2x80x9cnatural and unnatural amino acidxe2x80x9d refers to both the naturally occurring amino acids and other non-proteinogenic xcex1-amino acids commonly utilized by those in the peptide chemistry arts when preparing synthetic analogues of naturally occurring peptides, including D and L forms. The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, y-carboxyglutamic acid, arginine, omithine and lysine. Examples of unnatural alpha-amino acids include hydroxylysine, citrulline, kynurenine, (4-aminophenyl)alanine, 3-(2xe2x80x2-naphthyl)alanine, 3-(1xe2x80x2-naphthyl)alanine, methionine sulfone, (t-butyl)alanine, (t-butyl)glycine, 4-hydroxyphenyl-glycine, aminoalanine, phenylglycine, vinylalanine, propargyl-gylcine, 1,2,4-triazolo-3-alanine, thyronine, 6-hydroxytryptophan, 5-hydroxytryptophan, 3-hydroxy-kynurenine, 3-aminotyrosine, trifluoromethylalanine, 2-thienylalanine, (2-(4-pyridyl)ethyl)cysteine, 3,4-dimethoxy-phenylalanine, 3-(2xe2x80x2-thiazolyl)alanine, ibotenic acid, 1-amino-1-cyclopentane-carboxylic acid, 1-amino-1-cyclohexanecarboxylic acid, quisqualic acid, 3-(trifluoromethylphenyl)alanine, (cyclohexyl)glycine, thiohistidine, 3-methoxytyrosine, norleucine, norvaline, alloisoleucine, homoarginine, thioproline, dehydro-proline, hydroxyproline, homoproline, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3,4-tetrahydroquinoline-2-carboxylic acid, xcex2-amino-n-butyric acid, cyclohexylalanine, 2-amino-3-phenylbutyric acid, phenylalanine substituted at the ortho, meta, or para position of the phenyl moiety with one or two of the following groups: a (C1 to C4)alkyl, a (C1 to C4)alkoxy, a halogen or a nitro group, or substituted once with a methylenedioxy group; xcex2-2- and 3-thienylalanine; xcex2-2- and 3-fliranylalanine; xcex2-2-, 3- and 4-pyridylalanine; xcex2-(benzothienyl-2- and 3-yl)alanine; xcex2-(1- and 2-naphthyl)alanine; O-alkylated derivatives of serine, threonine or tyrosine; S-alkylated cysteine, S-alkylated homocysteine, the O-sulfate, O-phosphate and O-carboxylate esters of tyrosine; 3-(sulfo)tyrosine, 3-(carboxy)tyrosine, 3-(phospho)tyrosine, the 4-methane-sulfonic acid ester of tyrosine, 4-methanephosphonic acid ester of tyrosine, 3,5-diiodotyrosine, 3-nitrotyrosine, xcex5-alkyllysine, and delta-alkyl omithine. Any of these xcex1-amino acids may be substituted with a methyl group at the alpha position, a halogen at any position of the aromatic residue on the xcex1-amino side chain, or an appropriate protective group at the O, N, or S atoms of the side chain residues. Appropriate protective groups are discussed above.
The compounds of this invention may be modified by appropriate flunctionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of exertion. In addition, the compounds may be altered to pro-drug form such that the desired compound is created in the body of the patient as the result of the action of metabolic or other biochemical processes on the pro-drug. Some examples of pro-drug forms include ketal, acetal, oxime, and hydrazone forms of compounds which contain ketone or aldehyde groups, especially where they occur in the group donated as xe2x80x9cAxe2x80x9d in Formula I or the modified aspartic acid residue attached to the group denoted as xe2x80x9cAxe2x80x9d.
With regard to the p and q groups of Formula I, typical embodiments include compounds wherein q is 1 and p is 2.
Compounds of this invention with respect to the R, R1 and R1xe2x80x2 groups in Formula I, include those wherein:
R is lower alkyl;
R1 is phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, heteroaryl, or (heteroaryl)alkyl; and
R1xe2x80x2 is hydrogen or lower alkyl.
More typically, the compounds of this invention with respect to the R, R1, and R1xe2x80x2 groups include those wherein:
R is methyl;
R1 is phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, or (1 or 2 naphthyl)alkyl; and
R1xe2x80x2 is hydrogen.
Compounds of this invention with respect to the A group in Formula I, include those of Formula IIa wherein:
R3 is lower alkyl, cycloalkyl, phenyl, substituted phenyl, (CH2)nNH2, (CH2)mOR10, (CH2)mSR11, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R3a is hydrogen;
R10 is hydrogen, lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
R11 is lower alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl); and
n=1-4 and m=1 or 2.
Compounds of this invention with respect to the A group in Formula I also include those of Formula IIb wherein:
R4 is phenyl, substituted phenyl, (CH2)mphenyl, (CH2)m(substituted phenyl), cycloalkyl, or 2-indanyl; and
m=1 or 2.
Another group of compounds with respect to the A group in Formula I include those of Formula IId wherein:
R6 is hydrogen, fluorine, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(1 or 2-naphthyl), OR10, or SR11;
R10 and R11 are independently cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)ncycloalkyl, (CH2)nphenyl, (CH2)n(substituted phenyl), or (CH2)n(1 or 2-naphthyl); and
n=1-4.
A fourth group of compounds with respect to the A group in Formula I include those of Formula IIe wherein:
R7 is hydrogen, oxo, cycloalkyl, phenyl, substituted phenyl, or naphthyl; and
Xxe2x95x90CH2, (CH2)2, (CH2)3, or S.
Another group of compounds with respect to the A group in Formula I include those of Formula IIh wherein:
a=0 and b=1 or2.
Compounds of this invention with respect to the B group in Formula I include those wherein:
B is hydrogen, 2-benzoxazolyl, substituted 2-oxazolyl, CH2ZR15, CH2OCO(aryl), or CH2OPO(R16)R17, where Z is an oxygen or a sulfur atom;
R15 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, (CH2)nphenyl, (CH2)n(substituted phenyl), (CH2)n(1 or 2-naphthyl), or (CH2)n(heteroaryl); and
R16 and R17 are independently alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, phenylalkyl, substituted phenylalkyl, or (cycloalkyl)alkyl.
Another group of compounds with respect to the B group in Formula I include those of Formula IIIa-c wherein:
Y1 is O or NR23;
Y2 is CH2, O, or NR23;
R18 and R19 are independently hydrogen, alkyl, or phenyl, or R18 and R19 taken together are xe2x80x94(CHxe2x95x90CH)2xe2x80x94;
R20 is hydrogen, alkyl, phenyl, substituted phenyl, (CH2)nphenyl, or (CH2)n(substituted phenyl); and
R21, R22 and R23 are independently hydrogen or alkyl.
The compounds of Formula I may be synthesized using conventional techniques, as well as by the following Reaction Schemes. 
In the above Reaction Scheme 1, R2 represents hydrogen or a carboxy protecting group, wherein the carboxy protecting group is as defined above. xe2x80x9cPG1xe2x80x9d stands for an amino protecting group, xe2x80x9cPG2xe2x80x9d stands for a hydroxy-protecting group, and xe2x80x9cAxe2x80x9d stands for a natural or unnatural amino acid of formula IIa through IIi, as discussed above.
The modified aspartic acids of Formula V can be prepared by methods well known in the art. See, for example, European Patent Application 519,748; PCT Patent Application No. PCT/EP92/02472; PCT Patent Application No. PCT/US91/06595; PCT Patent Application No. PCT/US91/02339; European Patent Application No. 623,592; World Patent Application No. WO 93/09135; PCT Patent Application No. PCT/US94/08868; European Patent Application No. 623,606; European Patent Application No. 618,223; European Patent Application No. 533,226; European Patent Application No. 528,487; European Patent Application No. 618,233; PCT Patent Application No. PCT/EP92/02472; World Patent Application No. WO 93/09135; PCT Patent Application No. PCT/US93/03589; and PCT Patent Application No. PCT/US93/00481, all of which are herein incorporated by reference. For example, in Step A, the carboxylic acid moiety of Formula IV is converted to its bromomethyl ketone which is then treated with either R15Zxe2x80x94H, (aryl)-CO2H, (heteroaryl)-CO2H, or R16(R17)PO2H in the presence of an inorganic base such as potassium carbonate or potassium fluoride in an inert solvent such as dimethyl formamide to give the corresponding intermediate of Formula V in which B is CH2ZR15, CH2OCO(aryl), CH2OCO(heteroaryl), or CH2OPO(R16)R17, respectively.
Reduction of the carbonyl group in Formula V (Step B) with a hydride reducing agent such as sodium borohydride gives rise to a diastereomeric mixture of alcohols which are further protected with a hydroxy-protecting group (PG2) as referenced above.
The coupling reaction carried out under Step D is performed in the presence of a standard peptide coupling agent such as the combination of the combination of dicyclohexylcarbodiimide(DCC) and 1-hydroxy-benzotriazole(HOBt), as well as the BOP (benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate) reagent, pyBOP (benzotriazolyloxy-tris(N-pyrolidinyl)phosphoniumhexafluorophosphate), HATU (O-7-Azabenzotriazol-1-yl-tetramethylisouronium-hexafluorophosphate), HBTU (O-benzotriazolyly-tetramethylisouronium-hexafluoroph and EEDQ (1-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline) reagents, the combination of 1-ethyl(3,3xe2x80x2-dimethyl-1xe2x80x2-aminopropyl)carbodiimide (EDAC) and HOBt, and the like, as discussed in J. Jones, xe2x80x9cAmino Acid and Peptide Synthesis,xe2x80x9d Steven G. Davis ed., Oxford University Press, Oxford, pp. 25-41 (1992); M. Bodanzky, xe2x80x9cPrinciples of Peptide Synthesis,xe2x80x9d Hafner et al. ed., Springer-Verlag, Berlin Heidelberg, pp. 9-52 and pp. 202-251 (1984); M. Bodanzky, xe2x80x9cPeptide Chemistry, A Practical Textbook,xe2x80x9d Springer-Verlag, Berlin Heidelberg, pp. 55-73 and pp. 129-180; and Stewart and Young, xe2x80x9cSolid Phase Peptide Synthesis,xe2x80x9d Pierce Chemical Company, (1984), all of which are herein incorporated by reference. The amino protecting group is then removed and the resulting amine is coupled to the (N-substituted) oxamic acid of Formula IX (Step E). Again, this coupling reaction uses the standard peptide coupling reactions mentioned above.
Conversion of the carboxylate of Formula X to the acyl sulfonamide (Step F) involves removal of the carboxy protecting group (R2) using standard conditions well known in the art. The resulting carboxylic acid is then treated with CDI (2 eq.) in THF at room temperature for 3 hours, followed by H2NS(O)qR (2 eq.) in DBU (2 eq.) at room temperature for 4 hours.
The acyl sulfonamide intermediate of Formula XI is reacted in Step G with TsOH (0.4 eq.) in methanol at room temperature for 30 minutes to de-protect the alcohol, which may be converted to the corresponding carbonyl of Formula I by employing the Dess-Martin periodinane reagent and DCM at room temperature for 30 minutes. 
In the above Reaction Scheme 2, R2 represents hydrogen or a carboxy protecting group, wherein the carboxy protecting group is as defined above. xe2x80x9cPG1xe2x80x9d stands for an amino protecting group, xe2x80x9cPG2xe2x80x9d stands for a hydroxy-protecting group, and xe2x80x9cAxe2x80x9d stands for a natural or unnatural amino acid of formula Ia through IIi, as discussed above.
The modified aspartic acids of Formula V can be prepared by methods well known in the art. See, for example, European Patent Application 519,748; PCT Patent Application No. PCT/EP92/02472; PCT Patent Application No. PCT/US91/06595; PCT Patent Application No. PCTIUS91/02339; European Patent Application No. 623,592; World Patent Application No. WO 93/09135; PCT Patent Application No. PCT/US94/08868; European Patent Application No. 623,606; European Patent Application No. 618,223; European Patent Application No. 533,226; European Patent Application No. 528,487; European Patent Application No. 618,233; PCT Patent Application No. PCT/EP92/02472; World Patent Application No. WO 93/09135; PCT Patent Application No. PCT/US93/03589; and PCT Patent Application No. PCT/US93/00481, all of which are herein incorporated by reference. For example, in Step A, the carboxylic acid moiety of Formula IV is converted to its bromomethyl ketone which is then treated with either R15Zxe2x80x94H, (aryl)-CO2H, (heteroaryl)-CO2H, or R16(R17)PO2H in the presence of an inorganic base such as potassium carbonate or potassium fluoride in an inert solvent such as dimethyl formamide to give the corresponding intermediate of Formula V in which B is CH2ZR15, CH2OCO(aryl), CH2OCO(heteroaryl), or CH2OPO(R16)R17, respectively.
Reduction of the carbonyl group in Formula V (Step B) with a hydride reducing agent such as sodium borohydride gives rise to a diastereomeric mixture of alcohols which are further protected with a hydroxy-protecting group (PG2) as referenced above.
Conversion of the carboxylate of Formula VI to the acyl sulfonamide (Step F) involves removal of the carboxy protecting group (R2) using standard conditions well known in the art. The resulting carboxylic acid is then treated with CDI (2 eq.) in THF at room temperature for 3 hours, followed by H2NS(O)pR (2 eq.) in DBU (2 eq.) at room temperature for 4 hours.
The coupling reaction carried out under Step D is performed in the presence of a standard peptide coupling agent such as the combination of the combination of dicyclohexylcarbodiimide(DCC) and 1-hydroxy-benzotriazole(HOBt), as well as the BOP (benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate) reagent, pyBOP (benzotriazolyloxy-tris(N-pyrolidinyl)phosphoniumhexafluorophosphate), HATU (O-7-Azabenzotriazol-1-yl-tetramethylisouronium-hexafluorophosphate), HBTU (O-benzotriazolyly-tetramethylisouronium-hexafluorophosphate), and EEDQ (1-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline) reagents, the combination of 1-ethyl(3,3xe2x80x2-dimethyl-1xe2x80x2-aminopropyl)carbodiimide (EDAC) and HOBt, and the like, as discussed in J. Jones, xe2x80x9cAmino Acid and Peptide Synthesis,xe2x80x9d Steven G. Davis ed., Oxford University Press, Oxford, pp. 25-41 (1992); M. Bodanzky, xe2x80x9cPrinciples of Peptide Synthesis,xe2x80x9d Hafner et al. ed., Springer-Verlag, Berlin Heidelberg, pp. 9-52 and pp. 202-251 (1984); M. Bodanzky, xe2x80x9cPeptide Chemistry, A Practical Textbook,xe2x80x9d Springer-Verlag, Berlin Heidelberg, pp. 55-73 and pp. 129-180; and Stewart and Young, xe2x80x9cSolid Phase Peptide Synthesis,xe2x80x9d Pierce Chemical Company, (1984), all of which are herein incorporated by reference. The amino protecting group is then removed and the resulting amine is coupled to the (N-substituted) oxamic acid of Formula IX (Step E). Again, this coupling reaction uses the standard peptide coupling reactions mentioned above.
The acyl sulfonamide intermediate of Formula XI is reacted in Step G with TBAF in THF overnight to deprotect the alcohol, which may be converted to the as corresponding carbonyl of Formula I by employing the Dess-Martin periodinane reagent and DCM at room temperature for 30 minutes.
Alternatively, a stabilized cyclic acyl sulfonamide may first be formed and then added to the remainder of the molecule via amide bond formation with the carboxy terminus of the natural or unnatural amino acid A, as illustrated in Reaction Scheme 3. 
This reaction is further illustrated in Example 5 below.
Depending on the choice of solvent and other conditions known to the practitioner skilled in the art, compounds of this invention may also take a cyclized form, which forms are included in the instant invention. In particular, when B is hydrogen compounds of Formula I may exist in the cyclic Formula Ixe2x80x2 shown below: 
When B is a moiety other than hydrogen, and depending upon the choice of solvents (e.g., Rxe2x80x2OH), the compounds of the cyclic form also include compounds having Formula Ixe2x80x3 as shown below. 
In Formula Ixe2x80x3 above, Rxe2x80x2 includes alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, substituted (1 or 2 naphthyl)alkyl, heterocycle, substituted heterocycle, (heterocycle)alkyl, or substituted (heterocycle)alkyl.
In addition, it should be understood that the equilibrium forms of the compounds of this invention may include tautomeric forms. All such forms of these compounds are expressly included in the present invention.
Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle (hereinafter collectively referred to as xe2x80x9cpharmaceutically-acceptable carriersxe2x80x9d). Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchange, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin; buffer substances such as the various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyarylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, and the like.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by an implanted reservoir. Oral and parenteral administration are preferred. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carrier which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the forn of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible to topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-applied transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The compounds of this invention may be used in combination with either conventional anti-inflammatory agents or with matrix metalloprotease inhibitors, lipoxygenase inhibitors and antagonists of cytokines other than IL-1xcex2.
The compounds of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexons and rEPO) or with prostaglandins, to prevent or combat IL-1-mediated disease symptoms such as inflammation.
When the compounds of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical compositions according to this invention may be comprised of a combination of a compound of Formula I and another therapeutic or prophylactic agent mentioned above.
The disease states which may be treated or prevented by the instant pharmaceutical compositions include, but are not limited to, inflammatory diseases, autoimmune diseases and neurodegenerative diseases, and for inhibiting unwanted apoptosis involved in ischemic injury, such as ischemic injury to the heart (e.g., myocardial infarction), brain (e.g., stroke), and kidney (e.g., ischemic kidney disease). As a consequence of their ability to inhibit apoptosis, the present pharmaceutical compositions are also useful for the repopulation of hematopoietic cells of a patient following chemotherapy. Methods of administering an effective amount of the above-described pharmaceutical compositions to mammals, also referred to herein as patients, in need of such treatment (that is, those suffering from inflammatory diseases, autoimmune diseases, neurodegenerative diseases and for the repopulation of hematopoietic cells in cancer patients who have undergone chemotherapy) are another aspect of the instant invention. Finally, as a further consequence of their ability to inhibit apoptosis, the instant pharmaceutical compositions may be used in a method to prolong the viability of organs to be used in transplantations.
Inflammatory disease which may be treated or prevented include, for example, septic shock, septicemia, and adult respiratory distress syndrome. Target autoimmune diseases include, for example, rheumatoid, arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves"" disease, autoimmune gastritis, insulin-dependent diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis and multiple sclerosis. Target neurodegenerative diseases include, for example, amyotrophic lateral sclerosis, Alzheimer""s disease, Parkinson""s disease, and primary lateral sclerosis. The pharmaceutical compositions of this invention may also be used to promote wound healing. Target diseases associated with harmful, apoptosis, in other words, those associated with ischemic injury, includes myocardial infarction, stroke, and ischemic kidney disease. The pharmaceutical compositions of this invention may also be used to treat infectious diseases, especially those involved with viral infections.
The term xe2x80x9ceffective amountxe2x80x9d refers to dosage levels of the order of from about 0.05 milligrams to about 140 milligrams per kilogram of body weight per day for use in the treatment of the above-indicated conditions (typically about 2.5 milligrams to about 7 grams per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 milligrams of the compound per kilogram of body weight per day (about 0.5 milligrams to about 3.5 grams per patient per day).
The amount of the compounds of Formula I that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 milligrams to 5 grams of a compound of Formula I combined with an appropriate and convenient amount of a pharmaceutically-acceptable carrier which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 milligram to about 500 milligrams of an active compound of Formula I.
It will be understood, however, that the specific xe2x80x9ceffective amountxe2x80x9d for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing prevention or therapy.
Although this invention focuses on the use of the compounds disclosed herein for preventing and treating IL-1-mediated diseases, the compounds of this invention can also be used as inhibitory agents for other cysteine proteases.
The compounds of this invention are also useful as commercial reagents which effectively bind to the ICE/ced-3 family of cysteine protease or other cysteine proteases. As commercial reagents, the compounds of this invention, and their derivatives, may be used to block proteolysis of a target peptide or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. These and other uses which characterize commercial cystine protease inhibitors will be evident to those of ordinary skill in the art.